SUMMARY This project seeks to develop a novel disease-modifying compound for Alzheimer?s disease (AD). Synapse loss in AD brain has been tightly correlated with cognitive symptoms and is triggered initially by amyloid beta (A) peptide accumulation. We have described a pathway in which soluble A oligomers bind to Prion Protein, thereby engaging mGluR5 as a co-receptor, and activating PTK2B (Pyk2) and Fyn kinases to couple with Tau pathology and synapse loss. mGluR5 is a GPCR, and multiple groups have shown that interrupting mGluR5 function rescues preclinical AD phenotypes, making it an attractive drug target. However, mGluR5 has a physiological role as a glutamate receptor and full inhibition impairs function. Consequently, typical antagonists have a narrow therapeutic window. Yale has obtained an exclusive license to an extensive mGluR5-directed compound library with robust Intellectual Property protection. Within this chemical collection, we identified a highly potent, orally bioavailable mGluR5 ligand that does not alter basal or glutamate activity, but does block Ao/PrPC activation of mGluR5. This compound is considered a silent allosteric modulator, or SAM, for mGluR5, meaning ?silent? with regard to glutamate, while antagonistic with regard to Ao/PrPC. Preliminary studies demonstrate robust efficacy of this SAM compound for multiple preclinical mouse AD phenotypes. Drug treatment recovers synapse density, restores LTP and returns memory performance to WT levels. While closely related mGluR5 ligands have extensive selectivity and DMPK data, these are not yet developed for the SAM compound at this Early Stage, and we propose to obtain them here for this lead candidate. The overall goal is to develop disease-modifying oral therapy effective to slow, halt or partially reverse AD progression both in the MCI state and in mild dementia.